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PDBsum entry 2qic
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Antitumor protein, apoptosis
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PDB id
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2qic
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References listed in PDB file
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Key reference
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Title
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Histone h3k4me3 binding is required for the DNA repair and apoptotic activities of ing1 tumor suppressor.
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Authors
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P.V.Peña,
R.A.Hom,
T.Hung,
H.Lin,
A.J.Kuo,
R.P.Wong,
O.M.Subach,
K.S.Champagne,
R.Zhao,
V.V.Verkhusha,
G.Li,
O.Gozani,
T.G.Kutateladze.
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Ref.
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J Mol Biol, 2008,
380,
303-312.
[DOI no: ]
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PubMed id
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Abstract
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Inhibitor of growth 1 (ING1) is implicated in oncogenesis, DNA damage repair,
and apoptosis. Mutations within the ING1 gene and altered expression levels of
ING1 are found in multiple human cancers. Here, we show that both DNA repair and
apoptotic activities of ING1 require the interaction of the C-terminal plant
homeodomain (PHD) finger with histone H3 trimethylated at Lys4 (H3K4me3). The
ING1 PHD finger recognizes methylated H3K4 but not other histone modifications
as revealed by the peptide microarrays. The molecular mechanism of the histone
recognition is elucidated based on a 2.1 A-resolution crystal structure of the
PHD-H3K4me3 complex. The K4me3 occupies a deep hydrophobic pocket formed by the
conserved Y212 and W235 residues that make cation-pi contacts with the
trimethylammonium group. Both aromatic residues are essential in the H3K4me3
recognition, as substitution of these residues with Ala disrupts the
interaction. Unlike the wild-type ING1, the W235A mutant, overexpressed in the
stable clones of melanoma cells or in HT1080 cells, was unable to stimulate DNA
repair after UV irradiation or promote DNA-damage-induced apoptosis, indicating
that H3K4me3 binding is necessary for these biological functions of ING1.
Furthermore, N216S, V218I, and G221V mutations, found in human malignancies,
impair the ability of ING1 to associate with H3K4me3 or to induce nucleotide
repair and cell death, linking the tumorigenic activity of ING1 with epigenetic
regulation. Together, our findings reveal the critical role of the H3K4me3
interaction in mediating cellular responses to genotoxic stresses and offer new
insight into the molecular mechanism underlying the tumor suppressive activity
of ING1.
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Figure 1.
Fig. 1. The ING1 PHD finger recognizes H3K4me3. (a) Peptide
microarrays containing the indicated histone peptides were
probed with GST–ING1 PHD. Red spots indicate binding. me,
methylation; ac, acetylation; ph, phosphorylation; s, symmetric;
a, asymmetric. (b) Structure of the ING1 PHD finger in complex
with the histone H3K4me3 peptide. The PHD finger is shown as
solid surface. The histone peptide is depicted as ball-and-stick
model with C, O, and N atoms colored green, red, and blue,
respectively. (c) The PHD finger is shown as a ribbon with
residues mutated in human cancers colored brown. (d)
Interactions of the GST-fusion wild-type and mutant ING1 PHD
fingers with biotinylated histone peptides examined by Western
blot experiments.
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Figure 6.
Fig. 6. A model of the ING1 functioning. Binding of the
C-terminal PHD finger and the N-terminal SAID domain of ING1 to
H3K4me3 and a SAP30 subunit of the Sin3a/HDAC1/2, respectively,
tethers the histone modifying complex to the nucleosome for
subsequent deacetylation of acetylated lysine residues of
histone H3.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
380,
303-312)
copyright 2008.
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